Reaction Steps
To a solution of N1-(2-fluoro-4-(trifluoromethoxy)benzyl)-5-((1-methyl-1H-pyrazol-3-yl)methoxy)benzene-1,2-diamine (74.5 g, 0.18 mol) in ethanol (750 mL) was added a solution of racemic cis-3-hydroxyhexahydroisobenzofuran-1(3H)-one (28.4 g, 0.18 mol) and sodium sulfite (46.7 g, 0.36 mol) in H2O (750 mL). The reaction mixture was left open to air and stirred vigorously at RT. After 65 h, saturated sodium bicarbonate (600 mL) was added and the organic solvents were concentrated to dryness. The resulting suspension was partitioned between TBME (1.5 L) and H2O (1.5 L). The aqueous layer was partitioned between EtOAc (1.5 L) and HCl was added (160 mL, 6 M). The organic layer was separated and the aqueous was further extracted with ethyl acetate (500 mL). The combined organic layers were dried with MgSO4, filtered and concentrated to dryness. The resulting residue was dissolved in ethanol (450 mL) and H2O (100 mL), seeded (500 mg, 0.9 mmol) and stirred at room temperature for 1 h. H2O (300 mL) was then added portion wise over 30 min. The precipitate was filtered, rinsed with H2O/ethanol (2:1, 2×120 mL) and hexanes (2×200 mL) yielding the title compound as a light pink solid (59.8 g, 60.2%). The racemic material was separated into its constituent enantiomers through chiral stationary phase chromatography (stationary phase 600 g of Chiralpak IC, diameter: 110 mm, detector: Knauer superpreparative cell (0.5 mm), temperature: 35° Celsius, eluent: 0-20 min 40% heptane, 40% ethanol, 20% DCM (500 ml/min) (there was 0.10 v/v % acetic acid added to the eluents) to provide the title compound. MS (ESI): mass calcd. for C27H26F4N4O4, 546.2; m/z found, 547.0 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 7.63-7.59 (d, J=8.9, 1H), 7.34-7.30 (d, J=2.2, 1H), 7.11-7.06 (m, 1H), 7.06-7.02 (dd, J=8.9, 2.3, 1H), 6.95-6.90 (d, J=8.6, 1H), 6.88-6.84 (d, J=2.3, 1H), 6.81-6.74 (m, 1H), 6.31-6.28 (d, J=2.2, 1H), 5.38-5.28 (s, 2H), 5.09-5.04 (s, 2H), 3.89-3.84 (s, 3H), 3.24-3.14 (d, J=11.5, 1H), 3.08-3.02 (d, J=3.0, 1H), 2.65-2.51 (m, 1H), 1.90-1.78 (m, 2H), 1.78-1.70 (m, 1H), 1.69-1.58 (d, J=14.2, 2H), 1.56-1.39 (m, 2H).
